A CDC/APIC sponsored study revealed in June 2007 a pressing health crisis for the United States: Staphylococcus aureus is the leading cause of bloodstream, lower respiratory tract, skin and soft tissue infections. The broad spectrum of clinically important staphylococcal diseases includes also endocarditis, septic arthritis, toxic shock syndrome, scalded skin syndrome and food poisoning. S. aureus strains exhibiting multiple antibiotic resistances, methicillin-resistant S. aureus (MRSA), are isolated in up to 60% of community and 80% of hospital infections. 4.6 % of individuals admitted into American hospitals suffer staphylococcal infections, claiming an aggregate mortality of about 100,000 lives this year. Vancomycin and other glycopeptide inhibitors of cell wall synthesis are considered last-resort-therapies for MRSA, however strains with intermediate (VISA) or full resistance (VRSA) to vancomycin have caused infections for which antimicrobial treatment is no longer effective. The search for protective immunity against invasive S. aureus disease has been a goal since the discovery of this microbe. Whole-cell live or killed vaccines, however, failed to generate protective immune responses in humans and, because of safety concerns, are no longer considered for staphylococcal vaccine development. Research conducted under NIAID AI52747 studied the molecular biology of heme-iron scavenging in staphylococci and identified the molecular properties of iron-regulated surface determinants (IsdA-I). Other work sought to develop a broadly protective subunit vaccine by studying surface proteins conserved among different S. aureus strains as antigens in a murine model of abscess formation. Immunization with surface proteins, including the heme-transport proteins IsdA and IsdB, generated significant protective immunity that correlated with the induction of specific antibodies. When assembled into a combined vaccine, the surface protein vaccine afforded high levels of protection against invasive disease or lethal challenge with human clinical S. aureus isolates. This proposal aims to understand the molecular basis of staphylococcal vaccines from surface proteins and to appreciate the function of surface proteins and other secreted polypeptides in animal models of infection. Specifically, the role of heme scavenging in immunity against staphylococcal disease, the molecular biology of staphylococcal immune suppression by SasH, and the contribution of hlb-converting phages towards staphylococcal immune evasion will be investigated.